Enlarged-hetero-ring prosta-cyclin analogs

ABSTRACT

Prostaglandin (PG 1 , derivatives having (1) a 5-keto feature, for example ##STR1## or (2) a 9-deoxy-5,9-epoxy feature together with a 4-halo or 5-hydroxy feature, for example ##STR2## or a 4,5-didehydro feature, for example in an enol ether of the formula ##STR3## said derivatives having pharmacological activity. Processes for preparing them and the appropriate intermediates are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of copending application Ser. No. 819,856 filed July 28, 1977 now issued as U.S. Pat. No. 4,123,441, which was a continuation-in-part of then copending application Ser. No. 725,546 filed Sept. 22, 1976, since abandoned, which was a continuation-in-part of then copending application Ser. No. 716,960 filed Aug. 23, 1976, since abandoned.

BACKGROUND OF THE INVENTION

This invention relates to prostaglandin derivatives and to a process for preparing them.

Some of the compounds of this invention may be regarded as analogs of prostacyclin and prostacyclin-type compounds.

The essential material for this application, including the background of the invention, the disclosure of the invention, and the description of the preferred embodiments, including Preparations and Examples, is incorporated by reference from issued U.S. Pat. No. 4,123,441 under the provisions of M.P.E.P. 608.01(p).

SUMMARY OF THE INVENTION

It is the purpose of this invention to provide novel products having pharmacological activity. It is a further purpose to provide processes for preparing these products and their intermediates.

Accordingly, there is provided a compound of the formula: ##STR4## wherein R₂₀ is ##STR5## wherein L is (1) --(CH₂)_(d) --C(R₂)₂ --

(2) --O--CH₂ --Y-- or

(3) --CH═CH--

wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being the same or different with the proviso that one R₂ is not methyl when the other is fluoro, and Y is a valence bond, --CH₂ -- or --(CH₂)₂ --,

wherein O is ##STR6## wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive, wherein R₁ is

(1) --COOR₃

(2) --CH₂ OH

(3) --CH₂ N(R₉)(R₁₈) ##STR7## wherein R₃ is (a) hydrogen, (b) alkyl of one to 12 carbon atoms, inclusive, (c) cycloalkyl of 3 to 10 carbon atoms, inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive (e) phenyl, (f) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, ##STR8## wherein R₁₀ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, and wherein R₁₁ is hydrogen or benzoyl, or (n) a pharmacologically acceptable cation, wherein R₉ is hydrogen, methyl, or ethyl, and R₁₆ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with alkyl of one to 4 carbon atoms, inclusive;

wherein R₄ is ##STR9## wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ -- and terminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R₅ nor R₆ is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--) or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between CR₅ R₆ -- and the phenyl ring; wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ -- wherein R₇ is alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2 or 3, with the proviso that not more than two T's are other than alkyl and when s is 2 or 3 the T's are either the same or different; and

wherein X is

(1) trans--CH═CH--

(2) cis--CH═CH--

(3) --C.tbd.C-- or

(4) --CH₂ CH₂ --; including the lower alkanoates thereof.

In the formula IV as used herein, attachment to R₂₀ corresponds to bonds to the cyclopentane ring at the C-8, C-9, and C-12 positions following prostaglandin nomenclature, thus: ##STR10##

Within the scope of the prostaglandin derivatives described herein there are represented

(a) PGF.sub.α compounds when R₂₀ is ##STR11## (b) 11β-PGF.sub.α compounds when R₂₀ is ##STR12## (c) 11-Deoxy-11-keto-PGF.sub.α compounds when R₂₀ is ##STR13## (d) 11-Deoxy-11-methylene-PGF.sub.α compounds when R₂₀ is ##STR14## (e) 11-Deoxy-PGF.sub.α compounds when R₂₀ is ##STR15## (f) 11-Deoxy-10,11-Didehydro-PGF.sub.α compounds when R₂₀ is ##STR16## (g) 11-Deoxy-11-hydroxymethyl-PGF.sub.α compounds when R₂₀ is ##STR17##

For those compounds of formula IV wherein Q is ##STR18## i.e. wherein the C-15 hydroxyl group is attached to the side chain in alpha configuration, the configuration at C-15 is identical with that of the naturally occuring prostaglandins such as PGE₁ obtained from mammalian tissues. The 15-epimer compounds are represented by formula IV when Q is ##STR19## and are identified variously as "15-epi" or "15β" or "15R" by the appropriate prefix in the name. As is known in the art, "R" and "S" designations depend on the neighboring substituents. See R. S. Cahn, J. Chem. Ed. 41, 116 (1964).

An example of the enol ethers of formula IV is represented by the formula ##STR20## named (4Z)-9-deoxy-5,9α-epoxy-Δ⁴ -PGF₁, methyl ester.

As to the "Z" and "E" nomenclature for stereoisomerism about a double bond, see for example J. E. Blackwood et al., J. Am. Chem. Soc. 90, 509 (1968).

Also included within the scope of this invention are compounds of the formula ##STR21## wherein L, Q, R₁, R₄, R₂₀ and X are as defined herein. 

I claim:
 1. A 4Z compound of the formula ##STR22## wherein R₂₀ is ##STR23## wherein L is --(CH₂)_(d) --C(R₂)₂ --wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being the same or different with the proviso that one R₂ is not methyl when the other is fluoro,wherein Q is ##STR24## wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive, wherein R₃ is (a) hydrogen (b) alkyl of one to 12 carbon atoms, inclusive, or (c) cycloalkyl of 3 to 10 carbon atoms, inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl, (f) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, ##STR25## wherein R₁₀ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, and wheren R₁₁ is hydrogen or benzoyl, or (n) a pharmacologically acceptable cation; wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R₅ nor R₆ is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--), a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between CR₅ R₆ -- and the phenyl ring; wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ -- wherein R₇ is alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2 or 3, with the proviso that not more than two T's are other than alkyl and when s is 2 or 3 the T's are either the same or different; andwherein X is (1) trans--CH═CH-- (2) cis--CH═CH-- (3) --C.tbd.C-- or (4) --CH₂ CH₂ --; including the lower alkanoates thereof.
 2. A compound according to claim 1 wherein R₂₀ is ##STR26##
 3. A compound according to claim 1 wherein R₂₀ is ##STR27##
 4. A compound according to claim 1 wherein R₂₀ is ##STR28##
 5. A compound according to claim 1 wherein R₂₀ is ##STR29##
 6. A compound according to claim 1 wherein R₂₀ is ##STR30##
 7. A compound according to claim 1 wherein R₂₀ is ##STR31##
 8. A compound according to claim 1 wherein R₂₀ is ##STR32##
 9. A compound according to claim 8 wherein L is --(CH₂)_(n) --, n being 2, 3, or 4, and wherein Q is ##STR33## wherein R₈ is hydrogen, methyl, or ethyl.
 10. A compound according to claim 9 wherein L is --CH₂ CH₂ --.
 11. A compound according to claim 10 wherein R₅ and R₆ are hydrogen.
 12. A compound according to claim 11 wherein "s" is zero.
 13. A compound according to claim 12 wherein X is --C.tbd.C--.
 14. A compound according to claim 12 wherein X is --CH₂ CH₂ --.
 15. A compound according to claim 13 wherein R₃ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.
 16. A compound according to claim 12 wherein X is trans--CH═CH--.
 17. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -17-phenyl-18,19,20-trinor-13,14-didehydro-PGF₁, methyl ester, a compound according to claim
 15. 18. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -16-phenoxy-17,18,19,20-tetranor-13,14-didehydro-PGF₁, methyl ester, a compound according to claim
 15. 19. A compound according to claim 14, wherein R₃ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.
 20. A compound according to claim 19, wherein R₃ is methyl.
 21. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -17-phenyl-18,19,20-trinor-13,14-dihydro-PGF₁, methyl ester, a compound according to claim
 20. 22. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-PGF₁, methyl ester, a compound according to claim
 20. 23. A compound according to claim 19, wherein R₃ is sodium.
 24. A compound according to claim 16, wherein R₃ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.
 25. A compound according to claim 24, wherein R₃ is methyl.
 26. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -16-phenoxy-17,18,19,20-tetranor-PGF₁, methyl ester, a compound according to claim
 25. 27. A compound according to claim 24, wherein R₃ is sodium.
 28. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -17-phenyl-18,19,20-trinor-PGF₁, methyl ester, a compound according to claim
 25. 29. A compound according to claim 12, wherein X is cis--CH═CH--.
 30. A compound according to claim 29, wherein R₃ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.
 31. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -17-phenyl-18,19,20-trinor-cis-13-PGF₁, methyl ester, a compound according to claim
 30. 32. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -16-phenoxy-17,18,19,20-tetranor-cis-13-PGF₁, methyl ester, a compound according to claim
 30. 33. A compound according to claim 11, wherein "s" is one.
 34. A compound according to claim 33, wherein X is --CH₂ CH₂ --.
 35. A compound according to claim 34, wherein R₃ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.
 36. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGF.sub.1, methyl ester, a compound according to claim
 35. 37. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGF₁, methyl ester, a compound according to claim
 35. 38. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGF₁, methyl ester, a compound according to claim
 35. 39. A compound according to claim 33, wherein X is trans--CH═CH--.
 40. A compound according to claim 39, wherein R₃ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.
 41. A compound according to claim 40, wherein R₃ is methyl.
 42. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-PGF₁, methyl ester, a compound according to claim
 41. 43. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -16-(m-chlorophenoxy)-17,18,19,20-tetranor-PGF₁, methyl ester, a compound according to claim
 41. 44. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -16-(p-fluorophenoxy)-17,18,19,20-tetranor-PGF.sub.α, methyl ester, a compound according to claim
 41. 45. A compound according to claim 40, wherein R₃ is sodium.
 46. A compound according to claim 33, wherein X is cis--CH═CH--.
 47. A compound according to claim 46, wherein R₃ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.
 48. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-cis-13-PGF₁, methyl ester, a compound according to claim
 47. 49. A compound according to claim 10, wherein R₅ and R₆ are methyl.
 50. A compound according to claim 49, wherein "s" is zero.
 51. A compound according to claim 50, wherein X is --CH₂ CH₂ --.
 52. A compound according to claim 51, wherein R₃ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.
 53. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-PGF₁, methyl ester, a compound according to claim
 52. 54. A compound according to claim 50, wherein X is trans--CH═CH--.
 55. A compound according to claim 54, wherein R₃ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.
 56. A compound according to claim 55, wherein R₃ is methyl.
 57. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -16,16-dimethyl-17-phenyl-18,19,20-trinor-PGF₁, methyl ester, a compound according to claim
 56. 58. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -16-methyl-16-phenoxy-18,19,20-trinor-PGF₁, methyl ester, a compound according to claim
 56. 59. A compound according to claim 55, wherein R₃ is sodium.
 60. A compound according to claim 50, wherein X is cis--CH═CH--.
 61. A compound according to claim 60, wherein R₃ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.
 62. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -16,16-dimethyl-17-phenyl-18,19,20-trinor-cis-13-PGF₁, methyl ester, a compound according to claim
 61. 63. A compound according to claim 10, wherein R₅ and R₆ are fluoro.
 64. A compound according to claim 63, wherein "s" is zero.
 65. A compound according to claim 64, wherein X is --CH₂ CH₂ --.
 66. A compound according to claim 65, wherein R₃ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.
 67. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-PGF₁, methyl ester, a compound according to claim
 66. 68. A compound according to claim 64, wherein X is trans--CH═CH--.
 69. A compound according to claim 68, wherein R₃ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.
 70. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -16,16-difluoro-17-phenyl-18,19,20-trinor-PGF₁, methyl ester, a compound according to claim
 69. 71. A compound according to claim 8, wherein L is --CH₂ CF₂ -- and wherein Q is ##STR34## wherein R₈ is hydrogen, methyl, or ethyl.
 72. A compound according to claim 71, wherein R₅ and R₆ are hydrogen.
 73. A compound according to claim 72, wherein "s" is zero.
 74. A compound according to claim 73, wherein X is --CH₂ CH₂ --.
 75. A compound according to claim 74, wherein R₃ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.
 76. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-PGF₁, methyl ester, a compound according to claim
 75. 77. A compound according to claim 73, wherein X is trans--CH═CH--.
 78. A compound according to claim 77, wherein R₃ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.
 79. A compound according to claim 78, wherein R₃ is methyl.
 80. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -2,2-difluoro-17-phenyl-18,19,20-trinor-PGF₁, methyl ester, a compound according to claim
 79. 81. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-PGF₁, methyl ester, a compound according to claim
 79. 82. A compound according to claim 78, wherein R₃ is sodium.
 83. A compound according to claim 73, wherein X is cis--CH═CH--.
 84. A compound according to claim 83, wherein R₃ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.
 85. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-cis-13-PGF₁, methyl ester, a compound according to claim
 84. 86. A compound according to claim 71, wherein R₅ and R₆ are methyl.
 87. A compound according to claim 86, wherein "s" is zero.
 88. A compound according to claim 87, wherein X is --CH₂ CH₂ --.
 89. A compound according to claim 88, wherein R₃ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.
 90. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-PGF₁, methyl ester, a compound according to claim
 89. 91. A compound according to claim 87, wherein X is trans--CH═CH--.
 92. A compound according to claim 91, wherein R₃ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.
 93. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-PGF₁, methyl ester, a compound according to claim
 92. 94. A compound according to claim 87, wherein X is cis--CH═CH--.
 95. A compound according to claim 94, wherein R₃ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.
 96. (4Z)-9-Deoxy-5,9α-epoxy-Δ⁴ -2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-cis-13-PGF₁, methyl ester, a compound according to claim
 95. 97. A 4E compound of the formula ##STR35## wherein R₂₀ is ##STR36## wherein L is --(CH₂)_(d) --C(R₂)₂ -- wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being the same or different with the proviso that one R₂ is not methyl when the other is fluoro,wherein Q is ##STR37## wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive, wherein R₃ is (a) hydrogen, (b) alkyl of one to 12 carbon atoms, inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl, (f) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, ##STR38## wherein R₁₀ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, and wherein R₁₁ is hydrogen or benzoyl, or (n) a pharmacologically acceptable cation; wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R₅ nor R₆ is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--), a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between CR₅ R₆ -- and the phenyl ring; wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ -- wherein R₇ is alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2 or 3, with the proviso that not more than two T's are other than alkyl and when s is 2 or 3 the T's are either the same or different; andwherein X is (1) trans--CH═CH-- (2) cis--CH═CH-- (3) --C.tbd.C-- or (4) --CH₂ CH₂ --; including the lower alkanoates thereof. 